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Identification of the SV2 protein receptor-binding site of botulinum neurotoxin type E.

Authors :
Mahrhold S
Strotmeier J
Garcia-Rodriguez C
Lou J
Marks JD
Rummel A
Binz T
Source :
The Biochemical journal [Biochem J] 2013 Jul 01; Vol. 453 (1), pp. 37-47.
Publication Year :
2013

Abstract

The highly specific binding and uptake of BoNTs (botulinum neurotoxins; A-G) into peripheral cholinergic motoneurons turns them into the most poisonous substances known. Interaction with gangliosides accumulates the neurotoxins on the plasma membrane and binding to a synaptic vesicle membrane protein leads to neurotoxin endocytosis. SV2 (synaptic vesicle glycoprotein 2) mediates the uptake of BoNT/A and /E, whereas Syt (synaptotagmin) is responsible for the endocytosis of BoNT/B and /G. The Syt-binding site of the former was identified by co-crystallization and mutational analyses. In the present study we report the identification of the SV2-binding interface of BoNT/E. Mutations interfering with SV2 binding were located at a site that corresponds to the Syt-binding site of BoNT/B and at an extended surface area located on the back of the conserved ganglioside-binding site, comprising the N- and C-terminal half of the BoNT/E-binding domain. Mutations impairing the affinity also reduced the neurotoxicity of full-length BoNT/E at mouse phrenic nerve hemidiaphragm preparations demonstrating the crucial role of the identified binding interface. Furthermore, we show that a monoclonal antibody neutralizes BoNT/E activity because it directly interferes with the BoNT/E-SV2 interaction. The results of the present study suggest a novel mode of binding for BoNTs that exploit SV2 as a cell surface receptor.

Details

Language :
English
ISSN :
1470-8728
Volume :
453
Issue :
1
Database :
MEDLINE
Journal :
The Biochemical journal
Publication Type :
Academic Journal
Accession number :
23621114
Full Text :
https://doi.org/10.1042/BJ20130391